Accompanying the persistent growth in the world's population is a dramatic increase in the number of aged persons. Physiological function is altered with advancing age, including profound changes in the regulation of the sympathetic nervous system (SNS), supporting the concept that normal aging alters the regulation of sympathetic nerve outflow. However, the effects of advancing age on central mechanisms regulating sympathetic nerve discharge (SND) remain unknown. This is a significant omission because understanding how central sympathetic circuits change during normal aging is essential before relationships between normal and pathological conditions can be understood. The objective of the present research plan is to determine how advancing age, and the transition from a healthy aged state to senescence, alters central neural mechanisms regulating SND under basal conditions and in response to acute physical stress. Our basic approach (using electrophysiological, brain microinjection, molecular biological, and protein chemistry techniques) capitalizes on knowledge of central neural sympathetic regulatory principles and strategies to probe the fundamental mechanistic interactions between aging and SND regulation. The proposed studies will test the novel, overall HYPOTHESIS that: Age-dependent changes in the regulation of medullary sympathetic neural circuits (caudal pressor area, caudal ventral lateral medulla, and the rostral ventral lateral medulla) provide the mechanistic basis for mediating age-associated alterations in SND regulation in Fischer 344 (F344) rats. We propose three working hypotheses. Hypothesis 1: Advancing age transforms the medullary regulation of basal SND to a functional state characterized by enhanced activation and reduced inhibition. Hypothesis 2: Senescence reduces the responsivity and capability of medullary sympathetic neural circuits to regulate basal SND. Hypothesis 3: The responsiveness of medullary sympathetic neural circuits to acute stress is altered with advancing age, demonstrating age-related changes in medullary strategies to acute stress. These studies will establish age-related changes in mechanisms regulating the function of medullary sympathetic neural circuits under three aspects of aging: (1) progressive, healthy aging, (2) senescence, and (3) the ability of the aged (healthy/senescent) SNS to respond to acute stress. These findings will exert a sustained and powerful influence on the field by establishing new frontiers relating the effect of advancing age on mechanisms regulating the SNS, and by providing insight and direction for determining relationships between chronic disease development and age-associated changes in SNS function. PUBLIC HEALTH RELEVANCE: The sympathetic nervous system is critically involved in physiological function and the regulation of this system is markedly changed with advancing age. The proposed studies will determine how aging alters central nervous system mechanisms controlling sympathetic nerve activity. These studies will open new frontiers for understanding age-dependent effects on mechanisms regulating the sympathetic nervous system, and will provide the basis for determining relationships between chronic disease development and age-associated changes in sympathetic function.